Targeting Inflammation and Alloimmunity in Lung Transplant Recipients With Clazakizumab

用 Clazakizumab 治疗肺移植受者的炎症和同种免疫

• 批准号: 10488647
• 负责人: Ramsey Hachem
• 金额: $ 306.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-14 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10488647
• 关键词: Acute; Adrenal Cortex Hormones; Affect; Affinity; Allografting; Anti-Inflammatory Agents; Antibody Formation; Assessment tool; Autoantibodies; B cell differentiation; Binding; Biological Markers; Bronchiolitis; Canada; Categories; Cell Count; Cell physiology; Cells; Cessation of life; Chronic; Chronic Childhood Arthritis; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Complement-Dependent Cytotoxicity; Data; Development; Diagnostic tests; Disease; Dose; Double-Blind Method; Epitopes; Equilibrium; Experimental Models; FOXP3 gene; Fibrosis; Functional disorder; Future; Generations; Genetic Engineering; Hour; Human; IgG1; Immune; Immune response; Immune system; Immunity; Immunosuppression; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Interleukin-6; Interleukins; Isoantibodies; Kidney; Lead; Lesion; Link; Lung; Lung Transplantation; Lymphocyte; Maintenance; Mediating; Mediator of activation protein; Memory B-Lymphocyte; Morbidity - disease rate; Nature; Outcome; Pathogenicity; Pathway interactions; Patients; Phase; Placebos; Plasmablast; Production; Quality of life; Randomized; Randomized Controlled Trials; Refractory; Regimen; Regulatory T-Lymphocyte; Reperfusion Injury; Risk Assessment; Risk Factors; Saline; Signal Transduction; Surface; Survival Rate; T cell response; T-Lymphocyte; Tacrolimus; Testing; Time; Tissues; Transplant Recipients; Transplantation; Transplantation Immunology; Treatment Protocols; allograft rejection; antagonist; antibody-dependent cell cytotoxicity; antibody-mediated rejection; cell free DNA; clinical practice; cytokine; design; donor-specific antibody; graft dysfunction; humanized monoclonal antibodies; immunoregulation; improved; improved outcome; inflammatory milieu; insight; isoimmunity; kidney allograft; lung allograft; lung injury; mycophenolate mofetil; nano-string; novel; post-transplant; predictive test; preservation; prevent; primary endpoint; programs; prospective; randomized placebo controlled trial; randomized placebo-controlled clinical trial; receptor; response; secondary endpoint; standard of care; transcriptomics; transplant centers

PROJECT SUMMARY/ABSTRACT The 5-year survival after lung transplantation is a dismal 53% and chronic lung allograft dysfunction (CLAD) has emerged as the primary obstacle to better long-term outcomes. Clearly, current standard-of-care immunosuppressive regimens are failing lung transplant recipients, and there is a critical unmet need to improve survival. Primary graft dysfunction (PGD), episodes of acute cellular rejection (ACR), antibody-mediated rejection (AMR), and the development of donor-specific antibodies (DSA) are widely recognized risk factors for the development of CLAD. Furthermore, mechanistic studies link these inflammatory and alloimmune injuries to the fibrotic lesions that characterize CLAD. IL-6 is a pleiotropic cytokine that drives these deleterious inflammatory, immune, and fibrogenic responses thus, an especially attractive cytokine to target. Indeed, in experimental models, IL-6 signaling blockade has been shown to skew the Th17/Treg balance in favor of regulatory cell commitment thereby expanding Treg numbers, reducing allograft rejection, and diminishing memory B cell numbers and antibody formation (primary and recall). In human trials, IL-6R inhibition reduced alloantibody levels in highly sensitized kidney allograft recipients and improved graft and patient survival in kidney recipients with the most severe form of chronic antibody-mediated rejection. These data form the basis of our hypothesis that early IL-6 inhibition after lung transplantation will induce a protective/anti-inflammatory milieu that will have long- lasting effects on the host's immune system and allograft resulting in improved long-term graft and patient survival. To test this hypothesis, we propose to conduct a phase 2, multicenter, double blind, randomized, placebo-controlled trial examining the impact of early IL-6 inhibition with clazakizumab on CLAD-free allograft survival after lung transplantation. Clazakizumab (CSL Behring) is a genetically engineered, high affinity, humanized monoclonal antibody (IgG1) which binds to IL-6 and is a full and competitive antagonist of IL-6- induced cell function. The primary endpoint of the clinical trial is a composite of 1) CLAD, 2) re-transplantation, or 3) death. Key secondary endpoints include PGD, ACR, AMR, DSA. Furthermore, we plan to leverage the rich clinical data and human biospecimens that this clinical trial will generate to define the utility of several noninvasive biomarkers as risk assessment, diagnostic, and predictive testing strategies. Finally, we will conduct mechanistic studies to explain the effects of clazakizumab observed in the clinical trial. This trial represents the first application of IL-6 blockade in lung transplantation and has the potential change clinical practice and improve outcomes for lung transplant recipients. If CZK therapy is successful, our comprehensive and integrated mechanistic studies will allow us to elucidate mechanisms of improved graft outcomes. If therapy fails, we will be able to understand why. Either way, insights into the mechanisms of alloimune injury and chronic lung allograft dysfunction could lead to new preventative or treatment regimens.

项目总结/摘要 肺移植后的5年生存率是令人沮丧的53%，慢性肺移植物功能障碍（CLAD） 成为取得更好长期成果的主要障碍。很明显，目前的标准治疗 免疫抑制方案正在使肺移植受者失败， 生存原发性移植物功能障碍（PGD）、急性细胞排斥反应（ACR）发作、抗体介导的排斥反应 (AMR)，以及供体特异性抗体（DSA）的产生是广泛公认的 发展CLAD。此外，机制研究将这些炎症和同种免疫损伤与 纤维化病变是CLAD的特征。IL-6是一种多效性细胞因子， 免疫和纤维化反应，因此，这是一种特别有吸引力的靶向细胞因子。事实上，在实验 模型中，IL-6信号传导阻断已被证明会使Th 17/Treg平衡偏向于调节细胞， 从而扩大Treg数量，减少同种异体移植排斥，并减少记忆B细胞 数量和抗体形成（主要和召回）。在人体试验中，IL-6 R抑制降低同种抗体水平 在高致敏肾移植受者中， 最严重的慢性抗体介导的排斥反应。这些数据构成了我们假设的基础， 肺移植后早期IL-6抑制将诱导保护性/抗炎性环境， 对宿主免疫系统和同种异体移植物的持久影响，从而改善长期移植物和患者 生存为了检验这一假设，我们建议进行一项2期、多中心、双盲、随机、 一项安慰剂对照试验，检查clazakizumab早期抑制IL-6对无CLAD同种异体移植物的影响 肺移植后存活率克拉扎珠单抗（CSL Behring）是一种基因工程，高亲和力， 人源化单克隆抗体（IgG 1），其结合IL-6，并且是IL-6的完全和竞争性拮抗剂， 诱导细胞功能。临床试验的主要终点是1）CLAD，2）再次移植， 或3）死亡。关键次要终点包括PGD、ACR、AMR、DSA。此外，我们计划利用富人 本临床试验将产生的临床数据和人体生物标本，以确定几种非侵入性 生物标志物作为风险评估、诊断和预测性测试策略。最后，我们将进行机械化 解释临床试验中观察到的clazakizumab效应的研究。这场审判代表了 IL-6阻断剂在肺移植中的应用具有潜在的改变和提高临床实践的价值 肺移植受者的结局。如果CZK治疗成功，我们的全面和综合 机制研究将使我们能够阐明改善移植结果的机制。如果治疗失败，我们会 能够理解为什么。无论哪种方式，对同种异体损伤机制的深入了解， 慢性肺移植物功能障碍可能导致新的预防或治疗方案。